This invention relates to novel nitrogen-containing, thio-substituted, heterocyclic phosphonate compounds, including bisphosphonates, phosphonoalkylphosphinates, phosphonocarboxylates, and phosphonosulfonates. This invention further relates to pharmaceutical compositions containing these novel compounds, as well as to a method of treating or preventing certain metabolic bone disorders characterized by abnormal calcium and phosphate metabolism, utilizing a compound or pharmaceutical composition of the present invention. Specifically, this invention relates to a method of treating or preventing osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis, by utilizing a compound or pharmaceutical composition of the present invention.
A number of pathological conditions which can afflict warm-blooded animals involves abnormal calcium and phosphate metabolism. Such conditions may be divided into two broad categories.
1. Conditions which are characterized by anomalous mobilization of calcium and phosphate leading to general or specific bone loss, such as osteoporosis and Paget's disease,or excessively high calcium in the fluids of the body; such as hypercalcemia of tumor origin. Such conditions are sometimes referred to herein as pathological hard tissue demineralizations. PA1 2. Conditions which cause or result from deposition of calcium and phosphate anomalously in the body, such as rheumatoid arthritis and osteoarthritis. These conditions are sometimes referred to herein as pathological calcifications. PA1 (b) Q is covalent bond; 0, S, N, or NR.sup.1 ; PA1 (c) R is COOH, SO.sub.3 H, PO.sub.3 H.sub.2, or P(O)(OH)R.sup.4, wherein R.sup.4 is substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; PA1 (d) each R1 is independently selected from --SR.sup.6 ; --R.sup.8 SR.sup.6 ; nil; hydrogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; unsubstituted or substituted aryl; hydroxy; --CO.sub.2 R.sup.3 ; --O.sub.2 CR.sup.3 ; --NR.sup.3.sub.2 ; --OR.sup.3 ; --C(O)N(R.sup.3).sub.2 ; --N(R.sup.3)C(O)R.sup.3 ; substituted or unsubstituted benzyl; nitro; or combinations thereof; PA1 (e) R.sup.2 is one or more substituents on atoms in the Z moiety and is independently selected from --SR.sup.6 and --R.sup.8 SR.sup.6 ; where R.sup.6 is H; --CO.sub.2 R.sup.3 ; --O.sub.2 CR.sup.3 ; --NR.sup.3.sub.2 ; --N(R).sup.3 C(O)R.sup.3 ; and nil; hydrogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro; or combinations thereof; PA1 (f) each R.sup.3 is independently selected from hydrogen; substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; or R.sup.8 SR.sup.6 ; PA1 (g) R.sup.5 is selected from --SR.sup.6, R.sup.8 SR.sup.6, hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; and PA1 (h) R.sup.6 is independently selected from H; --C(O)R.sup.7 ; C(S)R.sup.7 ; C(O)NR.sup.7.sub.2 ; C(S)NR.sup.7.sub.2 ; .sup.C(O)(OR7); and C(S)(OR.sup.7); wherein R.sup.7 is hydrogen; or unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; PA1 (i) R.sup.8 is a substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; and PA1 (b) Q is covalent bond; O, S, N, or NR.sup.1 ; PA1 (c) R is COOH, SO.sub.3 H, PO.sub.3 H.sub.2, or P(O)(OH)R.sup.4 ; wherein R.sup.4 is substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; PA1 (d) each R1 is independently selected from --SR.sup.6 ; --R.sup.8 SR.sup.6 ; nil; hydrogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; unsubstituted or substituted aryl; hydroxy; --CO.sub.2 R.sup.3 ; --O.sub.2 CR.sup.3 ; --NR.sup.3.sub.2 ; --N(R.sup.3)C(O)R.sup.3 ; --OR.sup.3 ; --C(O)N(R.sup.3).sub.2 ; substituted or unsubstituted benzyl; nitro; or combinations thereof; PA1 (e) R.sup.2 is one or more substituents on atoms in the Z moiety and is independently selected from --SR.sup.6 ; --R.sup.8 SR.sup.6 ; --CO.sub.2 R.sup.3 ; --O.sub.2 CR.sup.3 ; --NR.sup.3.sub.2 ; --N(R).sup.3 C(O)R.sup.3 ; OR.sup.3 ; --C(O)N(R.sup.3).sub.2 ; nil; hydrogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; unsubstituted or substituted aryl; hydroxy; substituted or unsubstituted benzyl; nitro; or combinations thereof; PA1 (f) each R.sup.3 is independently selected from hydrogen; substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; or R.sup.8 SR.sup.6 ; PA1 (g) R.sup.5 is selected from --SR.sup.6 ; R.sup.8 SR.sup.6 ; hydrogen; hydroxy; amino; halogen; unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; amino; halogen and PA1 (h) R.sup.6 is independently selected from H; --C(O)R.sup.7 ; --C(S)R.sup.7 ; --C(O)NR.sup.7.sub.2 ; --C(S)NR.sup.7.sub.2 ; C(O)(OR.sup.7); or C(S)(OR.sup.7); wherein R.sup.7 is hydrogen; or unsubstituted or substituted C.sub.1 -C.sub.8 alkyl; PA1 (i) R.sup.8 is a substituted or unsubstituted C.sub.1 -C.sub.8 alkyl; and PA1 (a) the active ingredient proper; PA1 (b) the pharmaceutically-acceptable excipients; so long as the variants do not interfere in the activity of the particular active ingredient selected; PA1 (c) the type of the excipient, and the concomitant desirable thickness and permeability (swelling properties) of said excipients; PA1 (d) the time-dependent conditions of the excipient itself and/or within the excipients; PA1 (e) the particle size of the granulated active ingredient; and PA1 (f) the pH-dependent conditions of the excipients.
The first category included the most common metabolic bone disorder, osteoporosis; osteoporosis is a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. Marrow and bone spaces become larger, fibrous binding decreases, and compact bone becomes fragile. Osteoporosis can be subclassified as menopausal, senile, drug-induced (e.g. adrenocorticoid, as can occur in steroid therapy); disease-induced (arthritic and tumor), etc.; however, the manifestations are essentially the same. In general, there are two types of osteoporosis: primary and secondary. "Secondary osteoporosis" is the result of a separate identifiable disease process or agent. However, approximately 90% of all osteoporosis cases are "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, disuse osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis, affecting middle-aged and younger men and women.
For some osteoporotic individuals, the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
The mechanism of bone loss in osteoporotics is believed to involve an imbalance in the process of "bone remodeling". Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. This remodeling involves the erosion and filling of discrete sites on the surface of bones, by an organized group of cells called "basic multicellular units" or "BMUs". BMUs primarily consist of "osteoclasts", "osteoblasts", and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an "activated" BMU by an osteoclast, forming a resorption cavity. This cavity is then filled with bone by an osteoblast.
Normally, in adults, the remodeling cycle results in a small deficit in bone, due to incomplete filling of the resorption cavity. Thus, even in healthy adults, age-related bone loss occurs. However, in osteoporotics, there may be an increase in the number of BMUs that are activated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.
Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency.
Current osteoporosis treatment largely consists of calcium and estrogen administration.
The second category, involving conditions manifested by anomalous calcium and phosphate deposition, includes myositis ossificans progressive, calcinosis universalis, and such afflictions as arthritis (including, for example, rheumatoid arthritis and osteoarthritis), neuritis, bursitis, tendonitis, and other conditions which predispose involved tissue to deposition of calcium.
In addition to osteoporosis, bone loss can result from rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic, systemic and articular inflammatory disorder characterized by weakening of the joint capsules and ligaments, followed by destruction of cartilage, ligaments, tendon and bone, and a decrease in viscosity and other alterations in the synovial fluid. Rheumatoid arthritis symptoms include systemic weakness, fatigue, localized pain, stiffness and weakness and swelling and deformation of the joints of the body. Rheumatoid arthritis is most common in women in the fourth to sixth decade of life.
The pathogenesis of rheumatoid arthritis, leading to the destruction of the joints, is characterized by two phases: 1) an exudative phase involving the microcirculation and the synovial cells that allow an influx of plasma proteins and cellular elements into the joint and 2) a chronic inflammatory phase occurring in the sub-synovium characterized by pannus (granulation tissue) formation in the joint and sub-chondral bone, space, bone erosion, and cartilage destruction. The pannus may form adhesions and scar tissue which causes the joint deformities characteristic of rheumatoid arthritis.
The etiology of rheumatoid arthritis remains obscure. Infectious agents such as bacteria and viruses have been implicated. A current hypothesis is that the Epstein-Barr (EBV) virus is a causative agent for rheumatoid arthritis.
Current rheumatoid arthritis treatment consists predominantly of symptomatic relief by administration of non-steroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory drug treatment is mainly effective in the early stages of rheumatoid arthritis; it is unlikely it will produce suppression of joint inflammation if the disease is present for more than one year. Gold, methotrexate, immunosuppressants and corticosteroids have been tried with limited success.
On the other hand, osteoarthritis is an inherently non-inflammatory disorder of the movable joints characterized by deterioration and abrasion of articular cartilage, as well as by formation of new bone at the joint surface. As osteoarthritis progresses, the surface of the articular cartilage is disrupted and wear particles gain access to the synovial fluid which in turn stimulates phagocytosis by macrophage cells. Thus, an inflammatory response is eventually induced in osteoarthritis. Common clinical symptoms of osteoarthritis include cartilaginous and bony enlargements of the finger joints and stiffness on awakening, and pain from movement.
Common symptomatic treatments for osteoarthritis include analgesics, anti-inflammatories, steroids, and physical therapy.
A variety of phosphonic acid derivatives have been proposed for use in the treatment and prophylaxis of diseases involving abnormal calcium and phosphate metabolism. For example, numerous references, all incorporated by reference herein, disclose compositions containing polyphosphonates, in particular bisphosphonates such as ethane-1-hydroxy-1,1-diphosphonic acid ("EHDP"), and their use in inhibiting anomalous deposition and mobilization of calcium and phosphate in animal tissue: U.S. Pat. No. 3,683,080, issued Aug. 8, 1972 and U.S. Pat. No. 4,230,700, issued Oct. 28, 1980, both to Francis, and U.S. Pat. No. 4,868,164 to Ebetino, issued Sep. 19, 1989. Numerous other references describe heterocyclic-substituted diphosphonic acids useful for the treatment of osteoporosis and/or arthritis, and are hereby incorporated by reference herein: U.S. Pat. No. 4,868,164, to Ebetino, et al., issued Sep. 19, 1989; U.S. Pat. No. 5,104,863, to Benedict, et al., issued Apr. 14, 1992; U.S. Pat. No. 4,267,108, to Blum et al., issued May 12, 1981; European Patent Application Publication of Boehringer Mannhein GmbH No. 170,228, published Feb. 5, 1986; European Patent Application Publication No. 186,405, of Benedict and Perkins, published Jul. 2, 1986; U.S. Pat. No. 4,754,993, Bosies, et al. issued Nov. 15, 1988; U.S. Pat. No. 4,939,130, Jaeggi, et al., issued Jul. 3, 1990; U.S. Pat. No. 4,971,958, Bosies, et al. issued Nov. 20, 1990; DE 40 11 777, Jaeggi, K., published Oct. 18, 1990; WO 90/12017, of Dunn, et al., published Oct. 18, 1990; WO 91/10646, Youssefyeh, R., et al., published Jul. 25, 1991; AU-A-26738/88, Jaeggi, published Jun. 15, 1989, AU-A-45467/89 (assigned to Ciba-Geigy), published May 31, 1990; and U.S. Pat. No. 4,208,401 to Bauman issued Jun. 17, 1980.
In addition, several references describe sulfur-containing phosphonic acids which are said to be useful in the treatment of inflammation symptoms, See e.g. U.S. Pat. No. 4,746,654 to Breliere et al. (assigned to Sanofi), issue May 24, 1988; U.S. Pat. No. 4,876,247 to Barbier et al., issued Oct. 24, 1989; and EPO 100,718 to Breliere et al. (assigned to Sanofi), published Feb. 15, 1984. Also, U.S. Pat. No. 5,071,840 to Ebetino et al., issued Dec. 10, 1991, discloses sulfur-containing heterocycle-substituted diphosphonates in which the diphosphonate-substituted carbon moiety is attached to a carbon atom in a nitrogen-containing six-membered ring heterocycle. The compounds described therein are useful in the treatment of conditions involving abnormal calcium and phosphate metabolism, specifically osteoporosis and arthritis.
Further, European Pat. No. 0,298,553 to Ebetino, published Jan. 11, 1989 describes thiol-substituents amongst a myriad of other substituents, for suitable as substituents on methylene phosphonoalkylphosphinic acids. There is no teaching therein, however, that a thiol substituent increases anti-resorptive and antiarthritis activity over the numerous other substituents disclosed.
None of these references, however, disclose the utility of a thio-substituted, nitrogen-containing heterocyclic bisphosphonates, phosphonocarboxylates and phosphonosulfonates in preventing and treating osteoporosis and rheumatoid arthritis and osteoarthritis. The thio-substituents defined herein include thiol, alkyl thiols, thioesters, alkyl thioesters, dithioesters and alkyl dithioesters, thiocarbamates, alkyl thiocarbamates, dithiocarbamates, alkyl dithiocarbamates, thiocarbonates, alkyl thiocarbonates, dithiocarbonate, and alkyl dithiocarbonates. Further, the compounds of the present invention have osteoprotective activity of joint destruction in arthritic conditions and have that activity as an additional benefit in the treatment of arthritis over the above merely relieving the symptoms of inflammation. The term "osteoprotective activity" as used herein means disease-modifying activity on bone and surrounding soft issue at the site.
It has been surprisingly discovered that the compounds of the present invention have more potent bone antiresorptive activity, and also greater therapeutic utility in treating osteoporosis and arthritis, than heterocyclic bisphosphonate compounds not having a thio-substituent.
It is therefore an object of the present invention to provide new more potent, compounds which are potent bone resorption inhibiting agents useful in osteoporosis therapy and anti-arthritic agents useful in the treatment of osteoarthritis and rheumatoid arthritis. It is a further object of the present invention to provide pharmaceutical compositions useful for the treatment and prophylaxis of abnormal calcium and phosphate metabolism and for the treatment and prophylaxis of arthritis, especially rheumatoid arthritis and osteoarthritis. In addition, it is an object of the present invention to provide methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism in humans or other mammals, including osteoporosis, and arthritis, especially rheumatoid arthritis and osteoarthritis.
These and other objects of the present invention will become apparent from the detailed disclosure of the present invention provided hereinafter.